The Pima Indians have the highest reported prevalence and incident rate of non-insulin dependent diabetes mellitus (NIDDM) of any population of the world. The diabetes occurs more frequently in the offspring of diabetic mothers than in the offspring of non-diabetic parents. The reasons for this are unknown. In this project, we are longitudinally studying Pima Indians to determine the sequence of metabolic events that occurs with the development of NIDDM and also to isolate the predictor of the development of NIDDM. Studies are done on a yearly basis on the adult offspring of diabetic mothers and of non-diabetic parents to characterize their insulin and carbohydrate metabolism both in vivo and in vitro. Data collected to date has clearly demonstrated for the first time the relationships between degree of obesity as determined by careful body composition studies with insulin resistance. Obesity accounts at best for only about 50% of the variance in insulin resistance. Physical fitness, as determined by maximal oxygen uptake, appears to account for about 25% of the variance in insulin resistance. Most of insulin resistance appears to be due to a reduction in insulin-mediated glucose storage rather than a reduction in insulin-mediated glucose oxidation. Preliminary longitudinal analyses of the data so far have indicated that the development of impaired glucose tolerance is associated with weight gain, and decreased insulin action for glucose storage, but with little change in insulin action in isolated adipocytes from the same subjects. Approximately 14 subjects have developed diabetes and an equal number have developed impaired glucose tolerance. Statistical analyses are now underway to isolate the metabolic characteristic that is most predictive of these deteriorations of glucose tolerance.